CD73 inhibition by purine cytotoxic nucleoside analogue-based diphosphonates

• Published in: European journal of medicinal chemistry 2018-09, Vol.157, p.1051-1055
• Main Authors: Dumontet, Charles, Peyrottes, Suzanne, Rabeson, Céline, Cros-Perrial, Emeline, Géant, Pierre Yves, Chaloin, Laurent, Jordheim, Lars Petter
• Format: Article
• Language: English
• Subjects: 5'-Nucleotidase - antagonists & inhibitors; 5'-Nucleotidase - biosynthesis; 5'-Nucleotidase - metabolism; Biochemistry, Molecular Biology; Cancer; CD73; Cell Line, Tumor; Cell Survival - drug effects; Chemical Sciences; Cheminformatics; Diphosphonates - chemistry; Diphosphonates - pharmacology; Dose-Response Relationship, Drug; Enzyme inhibitor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Immunology; Life Sciences; Models, Molecular; Molecular Structure; Nucleotide; Purine Nucleosides - chemistry; Purine Nucleosides - pharmacology; Structural Biology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.035

The ecto-5′-nucleotidase CD73 has emerged as an important drug target in oncoimmunology as well as in other diseases. We describe new ADP analogues as CD73 inhibitors based on the replacement of the adenosine moiety, in the reference inhibitor APCP, by purine nucleoside analogues. Compounds were assessed for CD73 inhibition both on purified recombinant protein and on CD73-expressing cancer cells. The clofarabine-containing compound (2) was shown to be more potent than APCP with IC50 values of 0.18 μM (vs. 3.8 μM) on purified protein and 0.24 μM (vs. 23.6 μM) on CD73 expressed on cells. This work gives additional insights into structure-activity relationship of substrate-analogues as CD73 inhibitors. [Display omitted] •CD73 is involved in production of extracellular adenosine.•Adenosine stimulates tumor growth through immunosuppression.•New CD73 inhibitors are required for cancer treatment.